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Chimeric RNAs as potential biomarkers for tumor diagnosis

  • Zhou, Jianhua ;
  • Liao, Joshua ;
  • Zheng, Xuexiu ;
  • Shen, Haihong
  • Received : 2012.02.18
  • Published : 2012.03.31

Abstract

Cancers claim millions of lives each year. Early detection that can enable a higher chance of cure is of paramount importance to cancer patients. However, diagnostic tools for many forms of tumors have been lacking. Over the last few years, studies of chimeric RNAs as biomarkers have emerged. Numerous reports using bioinformatics and screening methodologies have described more than 30,000 expressed sequence tags (EST) or cDNA sequences as putative chimeric RNAs. While cancer cells have been well known to contain fusion genes derived from chromosomal translocations, rearrangements or deletions, recent studies suggest that trans-splicing in cells may be another source of chimeric RNA production. Unlike cis-splicing, trans-splicing takes place between two pre-mRNA molecules, which are in most cases derived from two different genes, generating a chimeric non-co-linear RNA. It is possible that trans-splicing occurs in normal cells at high frequencies but the resulting chimeric RNAs exist only at low levels. However the levels of certain RNA chimeras may be elevated in cancers, leading to the formation of fusion genes. In light of the fact that chimeric RNAs have been shown to be overrepresented in various tumors, studies of the mechanisms that produce chimeric RNAs and identification of signature RNA chimeras as biomarkers present an opportunity for the development of diagnoses for early tumor detection.

Keywords

Biomarkers;Chimeric RNA;Fusion gene;Trans-splicing

References

  1. Akiva, P., Toporik, A., Edelheit, S., Peretz, Y., Diber, A., Shemesh, R., Novik, A. and Sorek, R. (2006) Transcription- mediated gene fusion in the human genome. Genome Res. 16, 30-36. https://doi.org/10.1101/gr.4137606
  2. Asmann, Y. W., Hossain, A., Necela, B. M., Middha, S., Kalari, K. R., Sun, Z., Chai, H. S., Williamson, D. W., Radisky, D., Schroth, G. P., Kocher, J. P., Perez, E. A. and Thompson, E. A. (2011) A novel bioinformatics pipeline for identification and characterization of fusion transcripts in breast cancer and normal cell lines. Nucleic Acids Res. 39, e100. https://doi.org/10.1093/nar/gkr362
  3. Birney, E., Stamatoyannopoulos, J. A., Dutta, A., Guigo, R., Gingeras, T. R., Margulies, E. H., Weng, Z., Snyder, M., Dermitzakis, E. T., Thurman, R. E., Kuehn, M. S., Taylor, C. M., Neph, S., Koch, C. M., Asthana, S., Malhotra, A., Adzhubei, I., Greenbaum, J. A. andrews, R. M., Flicek, P., Boyle, P. J., Cao, H., Carter, N. P., Clelland, G. K., Davis, S., Day, N., Dhami, P., Dillon, S. C., Dorschner, M. O., Fiegler, H., Giresi, P. G., Goldy, J., Hawrylycz, M., Haydock, A., Humbert, R., James, K. D., Johnson, B. E., Johnson, E. M., Frum, T. T., Rosenzweig, E. R., Karnani, N., Lee, K., Lefebvre, G. C., Navas, P. A., Neri, F., Parker, S. C., Sabo, P. J., Sandstrom, R., Shafer, A., Vetrie, D., Weaver, M., Wilcox, S., Yu, M., Collins, F. S., Dekker, J., Lieb, J. D., Tullius, T. D., Crawford, G. E., Sunyaev, S., Noble, W. S., Dunham, I., Denoeud, F., Reymond, A., Kapranov, P., Rozowsky, J., Zheng, D., Castelo, R., Frankish, A., Harrow, J., Ghosh, S., Sandelin, A., Hofacker, I. L., Baertsch, R., Keefe, D., Dike, S., Cheng, J., Hirsch, H. A., Sekinger, E. A., Lagarde, J., Abril, J. F., Shahab, A., Flamm, C., Fried, C., Hackermuller, J., Hertel, J., Lindemeyer, M., Missal, K., Tanzer, A., Washietl, S., Korbel, J., Emanuelsson, O., Pedersen, J. S., Holroyd, N., Taylor, R., Swarbreck, D., Matthews, N., Dickson, M. C., Thomas, D. J., Weirauch, M. T., Gilbert, J., Drenkow, J., Bell, I., Zhao, X., Srinivasan, K. G., Sung, W. K., Ooi, H. S., Chiu, K. P., Foissac, S., Alioto, T., Brent, M., Pachter, L., Tress, M. L., Valencia, A., Choo, S. W., Choo, C. Y., Ucla, C., Manzano, C., Wyss, C., Cheung, E., Clark, T. G., Brown, J. B., Ganesh, M., Patel, S., Tammana, H., Chrast, J., Henrichsen, C. N., Kai, C., Kawai, J., Nagalakshmi, U., Wu, J., Lian, Z., Lian, J., Newburger, P., Zhang, X., Bickel, P., Mattick, J. S., Carninci, P., Hayashizaki, Y., Weissman, S., Hubbard, T., Myers, R. M., Rogers, J., Stadler, P. F., Lowe, T. M., Wei, C. L., Ruan, Y., Struhl, K., Gerstein, M., Antonarakis, S. E., Fu, Y., Green, E. D., Karaoz, U., Siepel, A., Taylor, J., Liefer, L. A., Wetterstrand, K. A., Good, P. J., Feingold, E.A., Guyer, M. S., Cooper, G. M., Asimenos, G., Dewey, C. N., Hou, M., Nikolaev, S., Montoya-Burgos, J. I., Loytynoja, A., Whelan, S., Pardi, F., Massingham, T., Huang, H., Zhang, N. R., Holmes, I., Mullikin, J. C., Ureta-Vidal, A., Paten, B., Seringhaus, M., Church, D., Rosenbloom, K., Kent, W. J., Stone, E. A., Batzoglou, S., Goldman, N., Hardison, R. C., Haussler, D., Miller, W., Sidow, A., Trinklein, N. D., Zhang, Z. D., Barrera, L., Stuart, R., King, D. C., Ameur, A., Enroth, S., Bieda, M. C., Kim, J., Bhinge, A. A., Jiang, N., Liu, J., Yao, F., Vega, V. B., Lee, C. W., Ng, P., Shahab, A., Yang, A., Moqtaderi, Z., Zhu, Z., Xu, X., Squazzo, S., Oberley, M. J., Inman, D., Singer, M. A., Richmond, T. A., Munn, K. J., Rada-Iglesias, A., Wallerman, O., Komorowski, J., Fowler, J. C., Couttet, P., Bruce, A. W., Dovey, O. M., Ellis, P. D., Langford, C. F., Nix, D. A., Euskirchen, G., Hartman, S., Urban, A. E., Kraus, P., Van Calcar, S., Heintzman, N., Kim, T. H., Wang, K., Qu, C., Hon, G., Luna, R., Glass, C. K., Rosenfeld, M. G., Aldred, S. F., Cooper, S. J., Halees, A., Lin, J. M., Shulha, H. P., Zhang, X., Xu, M., Haidar, J. N., Yu, Y., Ruan, Y., Iyer, V. R., Green, R. D., Wadelius, C., Farnham, P. J., Ren, B., Harte, R. A., Hinrichs, A. S., Trumbower, H., Clawson, H., Hillman-Jackson, J., Zweig, A. S., Smith, K., Thakkapallayil, A., Barber, G., Kuhn, R. M., Karolchik, D., Armengol, L., Bird, C. P., de Bakker, P. I., Kern, A. D., Lopez-Bigas, N., Martin, J. D., Stranger, B. E., Woodroffe, A., Davydov, E., Dimas, A., Eyras, E., Hallgrimsdottir, I. B., Huppert, J., Zody, M. C., Abecasis, G. R., Estivill, X., Bouffard, G. G., Guan, X., Hansen, N. F., Idol, J. R., Maduro, V. V., Maskeri, B., McDowell, J. C., Park, M., Thomas, P. J., Young, A. C., Blakesley, R. W., Muzny, D. M., Sodergren, E., Wheeler, D. A., Worley, K. C., Jiang, H., Weinstock, G. M., Gibbs, R. A., Graves, T., Fulton, R., Mardis, E. R., Wilson, R. K., Clamp, M., Cuff, J., Gnerre, S., Jaffe, D. B., Chang, J. L., Lindblad-Toh, K., Lander, E. S., Koriabine, M., Nefedov, M., Osoegawa, K., Yoshinaga, Y., Zhu, B. and de Jong, P. J. (2007) Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447, 799-816. https://doi.org/10.1038/nature05874
  4. Coady, T. H. and Lorson, C. L. (2010) Trans-splicing- mediated improvement in a severe mouse model of spinal muscular atrophy. J. Neurosci. 30, 126-130. https://doi.org/10.1523/JNEUROSCI.4489-09.2010
  5. Communi, D., Suarez-Huerta, N., Dussossoy, D., Savi, P. and Boeynaems, J. M. (2001) Cotranscription and intergenic splicing of human P2Y11 and SSF1 genes. J. Biol. Chem. 276, 16561-16566. https://doi.org/10.1074/jbc.M009609200
  6. Dotzlaw, H., Alkhalaf, M. and Murphy, L. C. (1992) Characterization of estrogen receptor variant mRNAs from human breast cancers. Mol. Endocrinol. 6, 773-785. https://doi.org/10.1210/me.6.5.773
  7. Edgren, H., Murumagi, A., Kangaspeska, S., Nicorici, D., Hongisto, V., Kleivi, K., Rye, I. H., Nyberg, S., Wolf, M., Borresen-Dale, A. L. and Kallioniemi, O. (2011) Identification of fusion genes in breast cancer by paired-end RNA-sequencing. Genome. Biol. 12, R6. https://doi.org/10.1186/gb-2011-12-1-r6
  8. Flouriot, G., Brand, H., Seraphin, B. and Gannon, F. (2002) Natural trans-spliced mRNAs are generated from the human estrogen receptor-alpha (hER alpha) gene. J. Biol. Chem. 277, 26244-26251. https://doi.org/10.1074/jbc.M203513200
  9. Ge, H., Liu, K., Juan, T., Fang, F., Newman, M. and Hoeck,W. (2011) FusionMap: detecting fusion genes from next-generation sequencing data at base-pair resolution. Bioinformatics 27, 1922-1928. https://doi.org/10.1093/bioinformatics/btr310
  10. Gerstein, M. B., Bruce, C., Rozowsky, J. S., Zheng, D., Du, J., Korbel, J. O., Emanuelsson, O., Zhang, Z. D., Weissman, S. and Snyder, M. (2007) What is a gene, post-ENCODE? History and updated definition. Genome Res. 17, 669-681. https://doi.org/10.1101/gr.6339607
  11. Gingeras, T. R. (2009) Implications of chimaeric non-colinear transcripts. Nature 461, 206-211. https://doi.org/10.1038/nature08452
  12. Ha, K. C., Lalonde, E., Li, L., Cavallone, L., Natrajan, R., Lambros, M. B., Mitsopoulos, C., Hakas, J., Kozarewa, I., Fenwick, K., Lord, C. J., Ashworth, A., Vincent-Salomon, A., Basik, M., Reis-Filho, J. S., Majewski, J. and Foulkes, W. D. (2011) Identification of gene fusion transcripts by transcriptome sequencing in BRCA1-mutated breast cancers and cell lines. BMC Med. Genomics 4, 75. https://doi.org/10.1186/1755-8794-4-75
  13. Hirano, M. and Noda, T. (2004) Genomic organization of the mouse Msh4 gene producing bicistronic, chimeric and antisense mRNA. Gene 342, 165-177. https://doi.org/10.1016/j.gene.2004.08.016
  14. Horiuchi, T. and Aigaki, T. (2006) Alternative trans-splicing: a novel mode of pre-mRNA processing. Biol. Cell 98, 135-140. https://doi.org/10.1042/BC20050002
  15. Iyer, M. K., Chinnaiyan, A. M. and Maher, C. A. (2011) ChimeraScan: a tool for identifying chimeric transcription in sequencing data. Bioinformatics 27, 2903-2904. https://doi.org/10.1093/bioinformatics/btr467
  16. Kannan, K., Wang, L., Wang, J., Ittmann, M. M., Li, W. and Yen, L. (2011) Recurrent chimeric RNAs enriched in human prostate cancer identified by deep sequencing. Proc. Natl. Acad. Sci. U.S.A. 108, 9172-9177. https://doi.org/10.1073/pnas.1100489108
  17. Kim, D. and Salzberg, S. L. (2011) TopHat-Fusion: an algorithm for discovery of novel fusion transcripts. Genome Biol. 12, R72. https://doi.org/10.1186/gb-2011-12-8-r72
  18. Kundu, M. and Liu, P. P. (2001) Function of the inv(16) fusion gene CBFB-MYH11. Curr. Opin. Hematol. 8, 201-205. https://doi.org/10.1097/00062752-200107000-00004
  19. Li, H., Wang, J., Ma, X. and Sklar, J. (2009) Gene fusions and RNA trans-splicing in normal and neoplastic human cells. Cell. Cycle. 8, 218-222. https://doi.org/10.4161/cc.8.2.7358
  20. Li, H., Wang, J., Mor, G. and Sklar, J. (2008) A neoplastic gene fusion mimics trans-splicing of RNAs in normal human cells. Science 321, 1357-1361. https://doi.org/10.1126/science.1156725
  21. Li, X., Zhao, L., Jiang, H. and Wang, W. (2009) Short homologous sequences are strongly associated with the generation of chimeric RNAs in eukaryotes. J. Mol. Evol. 68, 56-65. https://doi.org/10.1007/s00239-008-9187-0
  22. Li, Y., Chien, J., Smith, D. I. and Ma, J. (2011) FusionHunter: identifying fusion transcripts in cancer using paired-end RNA-seq. Bioinformatics 27, 1708-1710. https://doi.org/10.1093/bioinformatics/btr265
  23. Maher, C. A., Kumar-Sinha, C., Cao, X., Kalyana-Sundaram, S., Han, B., Jing, X., Sam, L., Barrette, T., Palanisamy, N. and Chinnaiyan, A. M. (2009) Transcriptome sequencing to detect gene fusions in cancer. Nature 458, 97-101. https://doi.org/10.1038/nature07638
  24. Maher, C. A., Palanisamy, N., Brenner, J. C., Cao, X., Kalyana-Sundaram, S., Luo, S., Khrebtukova, I., Barrette, T. R., Grasso, C., Yu, J., Lonigro, R. J., Schroth, G., Kumar- Sinha, C. and Chinnaiyan, A. M. (2009) Chimeric transcript discovery by paired-end transcriptome sequencing. Proc. Natl. Acad. Sci. U.S.A. 106, 12353-12358. https://doi.org/10.1073/pnas.0904720106
  25. McManus, C. J. and Graveley, B. R. (2011) RNA structure and the mechanisms of alternative splicing. Curr. Opin.Genet. Dev. 21, 373-379. https://doi.org/10.1016/j.gde.2011.04.001
  26. McPherson, A., Hormozdiari, F., Zayed, A., Giuliany, R., Ha, G., Sun, M. G., Griffith, M., Heravi Moussavi, A., Senz, J., Melnyk, N., Pacheco, M., Marra, M. A., Hirst, M., Nielsen, T. O., Sahinalp, S. C., Huntsman, D. and Shah, S. P. (2011) deFuse: an algorithm for gene fusion discovery in tumor RNA-Seq data. PLoS Comput. Biol. 7, e1001138. https://doi.org/10.1371/journal.pcbi.1001138
  27. Morerio, C., Acquila, M., Rapella, A., Tassano, E., Rosanda, C. and Panarello, C. (2006) Inversion (11)(p15q22) with NUP98-DDX10 fusion gene in pediatric acute myeloid leukemia. Cancer Genet. Cytogenet. 171, 122-125. https://doi.org/10.1016/j.cancergencyto.2006.07.002
  28. Murphy, L. C., Dotzlaw, H., Hamerton, J. and Schwarz, J. (1993) Investigation of the origin of variant, truncated estrogen receptor-like mRNAs identified in some human breast cancer biopsy samples. Breast. Cancer Res. Treat. 26, 149-161. https://doi.org/10.1007/BF00689688
  29. Nacu, S., Yuan, W., Kan, Z., Bhatt, D., Rivers, C. S., Stinson, J., Peters, B. A., Modrusan, Z., Jung, K., Seshagiri, S. and Wu, T. D. (2011) Deep RNA sequencing analysis of readthrough gene fusions in human prostate adenocarcinoma and reference samples. BMC Med. Genomics 4, 11. https://doi.org/10.1186/1755-8794-4-11
  30. Nowell, P. C. (1962) The minute chromosome (Phl) in chronic granulocytic leukemia. Blut. 8, 65-66. https://doi.org/10.1007/BF01630378
  31. Pflueger, D., Terry, S., Sboner, A., Habegger, L., Esgueva, R., Lin, P. C., Svensson, M. A., Kitabayashi, N., Moss, B. J., MacDonald, T. Y., Cao, X., Barrette, T., Tewari, A. K., Chee, M. S., Chinnaiyan, A. M., Rickman, D. S., Demichelis, F., Gerstein, M. B. and Rubin, M. A. (2011) Discovery of non-ETS gene fusions in human prostate cancer using next-generation RNA sequencing. Genome. Res. 21, 56-67. https://doi.org/10.1101/gr.110684.110
  32. Pink, J. J., Fritsch, M., Bilimoria, M. M., Assikis, V. J. and Jordan, V. C. (1997) Cloning and characterization of a 77-kDa oestrogen receptor isolated from a human breast cancer cell line. Br. J. Cancer 75, 17-27. https://doi.org/10.1038/bjc.1997.4
  33. Pink, J. J., Wu, S. Q., Wolf, D. M., Bilimoria, M. M. and Jordan, V. C. (1996) A novel 80 kDa human estrogen receptor containing a duplication of exons 6 and 7. Nucleic. Acids. Res. 24, 962-969. https://doi.org/10.1093/nar/24.5.962
  34. Anthony, K., Garcia-Blanco, M. A., Mansfield, S. G., Anderton, B. H. and Gallo, J. M. (2009) Correction of tau mis-splicing caused by FTDP-17 MAPT mutations by spliceosome- mediated RNA trans-splicing. Hum. Mol. Genet. 18, 3266-3273. https://doi.org/10.1093/hmg/ddp264
  35. Santo, E. E., Ebus, M. E., Koster, J., Schulte, J. H., Lakeman, A., van Sluis, P., Vermeulen, J., Gisselsson, D., Ora, I., Lindner, S., Buckley, P. G., Stallings, R. L., Vandesompele, J., Eggert, A., Caron, H. N., Versteeg, R., and Molenaar, J. J. (2011) Oncogenic activation of FOXR1 by 11q23 intrachromosomal deletion-fusions in neuroblastoma. Oncogene. doi: 10.1038/onc.2011.344. https://doi.org/10.1038/onc.2011.344
  36. Sboner, A., Habegger, L., Pflueger, D., Terry, S., Chen, D. Z., Rozowsky, J. S., Tewari, A. K., Kitabayashi, N., Moss, B. J., Chee, M. S., Demichelis, F., Rubin, M. A. and Gerstein, M. B. (2010) FusionSeq: a modular framework for finding gene fusions by analyzing paired-end RNA-sequencing data. Genome Biol. 11, R104. https://doi.org/10.1186/gb-2010-11-10-r104
  37. Shababi, M., Glascock, J. and Lorson, C. L. (2011) Combination of SMN trans-splicing and a neurotrophic factor increases the life span and body mass in a severe model of spinal muscular atrophy. Hum. Gene. Ther. 22, 135-144. https://doi.org/10.1089/hum.2010.114
  38. Shababi, M. and Lorson, C. L. (2012) Optimization of SMN Trans-Splicing Through the Analysis of SMN Introns. J. Mol. Neurosci. 46, 459-469. https://doi.org/10.1007/s12031-011-9614-3
  39. Shiga, Y., Sagawa, K., Takai, R., Sakaguchi, H., Yamagata, H. and Hayashi, S. (2006) Transcriptional readthrough of Hox genes Ubx and Antp and their divergent post-transcriptional control during crustacean evolution. Evol. Dev. 8, 407-414. https://doi.org/10.1111/j.1525-142X.2006.00114.x
  40. Skotheim, R. I., Thomassen, G. O., Eken, M., Lind, G. E., Micci, F., Ribeiro, F. R., Cerveira, N., Teixeira, M. R., Heim, S., Rognes, T. and Lothe, R. A. (2009) A universal assay for detection of oncogenic fusion transcripts by oligo microarray analysis. Mol. Cancer 8, 5. https://doi.org/10.1186/1476-4598-8-5
  41. Soda, M., Choi, Y. L., Enomoto, M., Takada, S., Yamashita, Y., Ishikawa, S., Fujiwara, S., Watanabe, H., Kurashina, K., Hatanaka, H., Bando, M., Ohno, S.,Ishikawa, Y., Aburatani, H., Niki, T., Sohara, Y., Sugiyama, Y. and Mano, H. (2007) Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448, 561-566. https://doi.org/10.1038/nature05945
  42. Takahashi, T., Sonobe, M., Kobayashi, M., Yoshizawa, A., Menju, T., Nakayama, E., Mino, N., Iwakiri, S., Sato, K., Miyahara, R., Okubo, K., Manabe, T. and Date, H. (2010) Clinicopathologic features of non-small-cell lung cancer with EML4-ALK fusion gene. Ann. Surg. Oncol. 17, 889-897. https://doi.org/10.1245/s10434-009-0808-7
  43. Wechsler, D. S., Engstrom, L. D., Alexander, B. M., Motto, D. G. and Roulston, D. (2003) A novel chromosomal inversion at 11q23 in infant acute myeloid leukemia fuses MLL to CALM, a gene that encodes a clathrin assembly protein. Genes Chromosomes Cancer 36, 26-36. https://doi.org/10.1002/gcc.10136
  44. Yang, Y. and Walsh, C. E. (2005) Spliceosome-mediated RNA trans-splicing. Mol. Ther. 12, 1006-1012. https://doi.org/10.1016/j.ymthe.2005.09.006
  45. Ye, Q., Chung, L. W., Li, S. and Zhau, H. E. (2000) Identification of a novel FAS/ER-alpha fusion transcript expressed in human cancer cells. Biochim. Biophys. Acta. 1493, 373-377. https://doi.org/10.1016/S0167-4781(00)00202-5

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